ABSTRACT Emerging evidence indicates that women are more likely to use a multipurpose prevention technology (MPT) for pregnancy and HIV/STI infection prevention than a product for pregnancy or HIV/STI infection prevention. The MPT development space is dominated by products that contain one or more hormonal contraceptives, which many women, including breastfeeding women, cannot or will not use. Amphora gel is an exception. Ampphora is a non-hormonal, vaginally-acting contraceptive product for women being developed by Evofem Biosciences Inc. It works by maintaining a low vaginal pH that is hostile to sperm, bacteria, and viruses. Evofem recently completed a Phase 3 contraceptive efficacy trial of Amphora that indicated typical use efficacy of 86.0% and per protocol efficacy (perfect use) of 98.7%, comparable to the efficacy of the most commonly used forms of hormonal contraception, oral pills. Amphora is currently being tested in Phase 2b trials for prevention of urogenital chlamydia and gonorrhea in women and preparing for trials for prevention of recurrent bacterial vaginosis (BV), which has completed enrollment. QGRFT is a stable analog of the non-antiretroviral (non-ARV) anti-HIV lectin griffithsin (GRFT). We completed a Phase 1 trial of a vaginally administered GRFT gel, and with PATH developed a novel vaginally administered GRFT fast dissolving insert (FDI) that significantly prevented simian human immunodeficiency virus (SHIV) infection in macaques and HSV-2 and HPV infection in mice. Our long term goal is to develop an Amphora/QGRFT FDI for adolescent girls and a wide range of women, including breastfeeding women, which provides non-hormonal contraception and reduces the risk of acquiring a broad range of viral and bacterial STIs. Herein we will evaluate the feasibility, safety, and in vivo efficacy of two innovative MPT prototypes: an Amphora/QGRFT FDI that could have contraceptive and anti-HIV/STI/BV properties and an Amphora-only FDI that could have contraceptive and anti-STI/BV properties. The prototypes will be manufactured and then evaluated in a series of in vitro assays, physiochemical property/stability evaluations, and in vivo studies to demonstrate FDI disintegration, drug retention in the vagina, safety, anti-HIV activity (pharmacodynamics studies in a macaque model and in vivo efficacy in macaques) and anti-HSV-2 activity (murine model). The Amphora/QGFRT FDI may offer more potent anti-HSV-2 activity than Amphora alone due to QGRFT?s anti-HSV-2 activity. Using data obtained in these studies, we will select one FDI to advance into contraceptive efficacy testing in rabbits and IND-enabling toxicology studies in rats. The novel non-hormonal FDI proposed here could (i) eliminate side effects associated with hormonal contraceptives, (ii) meet the needs of women who have infrequent sex or who are breastfeeding, and (iii) reduce the sexual acquitision of HIV/STIs and the emergence of ARV-resistant HIV. This woman-initiated FDI has the potential to improve women?s health and advance the MPT field. When approved, the FDI would be the first non-hormonal, on-demand and event-driven MPT with both contraceptive and broad spectrum anti/HIV/STI properties.